Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Genetics in Cancer Diagnosis and Treatment44th Semi-Annual Fall 2020 Temple University Family Medicine Review
Kara N. Maxwell, MD, PhDAssistant ProfessorDept of Medicine, Dept of GeneticsCancer Risk Evaluation ProgramPenn Medicine
Conflicts of Interest
I have no conflicts of interest to reportI do not consult for nor recommend any specific genetic testing
company discussed in this presentation
Genetics in Cancer Diagnosis and Treatment
Germline Cancer Genetics• Review of major cancer predisposition syndromes• Cancer risks associated with inherited mutations• Medical management for carriers• Germline Genetic Testing in 2020
Somatic Cancer Genetics• Treatment implications of genetic testing• Somatic Genetic Testing in 2020
Some terms Germline cancer risk mutations - mutations or set of
mutations in all cells from birth, inherited in families that lead to increased risk of development of cancer
• Relative risk – the fold risk increase associated with an inherited mutation over the risk of the cancer in the general population
• Absolute risk – the absolute risk of cancer associated with an inherited mutation (e.g. may be expressed in 5-year, 10-year or lifetime risk of a cancer)
Somatic alterations – acquired mutations in a tumor that may or may not be associated with development and progression of cancer
• Targetable or “Driver” mutations – acquired mutations in a tumor that drive the tumor’s growth and may lead to a response to therapy
• Passenger mutations – acquired mutations in a tumor that likely are not involved in tumor formation and are a result of the oncogenic process
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
e.gBRCA1, BRCA2
“Somatic” or “driver” changes that lead to cancer progression
e.gGain of HER2
Germline Cancer Genetics
Review of cancer predisposition
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
Inherited (germline) mutations in a number of tumor suppressor genes lead to autosomal dominant inherited cancer susceptibility
Autosomal Dominant Cancer syndromes 101
Example of a typical BRCA2 family
Examples of cancer predisposition syndromes with autosomal dominant inheritance
Gene(s) Syndrome Cancers
Most common referrals to Cancer Genetics ProgramsBRCA1 Hereditary breast-ovarian cancer syndrome Breast, ovarian
BRCA2 Hereditary breast-ovarian cancer syndrome Breast, ovarian, pancreatic, melanoma, male breast cancer
MLH1, MSH2, MSH6, PMS2
Lynch syndrome (Hereditary nonpolyposiscolon cancer - HNPCC)
Colon, endometrial, ovarian, liver, biliary, upper GI, pancreatic, brain,
urinary tractRare but important high risk cancer syndromes
TP53 Li-Fraumeni syndrome (LFS) sarcomas, osteosarcomas, leukemia, colon, adrenal, brain
CDH1 Hereditary diffuse gastric cancer syndrome diffuse gastric cancer
PTEN Cowden syndrome endometrial, thyroid, brain
Polyposis syndromes
APC Familial adenomatous polyposis (FAP) Colon, upper GI, pancreaticthyroid, brain
BMPR1A Juvenile polyposis syndrome Colon, gastric
STK11 Peutz-Jeghers syndromeColon, gastric, pancreatic, small intestine,
ovarian, cervical, testicular, lung
Rarer autosomal dominant inherited cancer predisposition syndromes
Gene(s) Syndrome Cancers
Endocrine and Renal
MEN1, RET Multiple endocrine neoplasia type 1,2a/b Pituitary, PNET, carcinoids (1)medullary thyroid, pheo (2)
VHL Von Hippel-Lindau syndrome PNET, pheo, clear cell RCC
FH Hereditary leiomyomatosis and renal cell cancer (HLRCC)
cutaneous leiomyomas, uterine leiomyomata (fibroids), and type 2
papillary RCC
FLCN Birt-Hogg-Dube syndrome Chromophobe and papillary clear cell RCC
MET Hereditary papillary renal cancer Type 1 papillary RCC
SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX
Hereditary pheochromocytoma and paraganglioma syndrome
Head and neck paragangliomas, thoracic/abdominal paragangliomas,
pheochromocytomasOther
PTCH1 Basal Cell Nevus Syndrome, GorlinSyndrome Skin BCCs
CDKN2A, BAP1, TERT, CDK4, CDK6 Hereditary melanoma Melanoma
NF1, NF2 Neurofibromatosis type1, 2 Brain, leukemia, benign tumors (1) Acoustic neuromas (2)
RB1 Retinoblastoma Retinoblastoma, sarcoma, melanoma
Summary of cancers associated with major autosomal dominantly inherited cancer predisposition syndromes
Gene(s) Syndrome Breast Ovarian Prostate Pancreatic Melanoma Colon Uterine Brain Kidney Stomach
BRCA1, BRCA2 HereditaryBreast/Ovarian
TP53 Li Fraumeni Syndrome
* Sarcoma
CDH1 Hereditary diffuse gastric cancer
PTEN Cowden Syndrome
STK11 Peutz JeghersSyndrome
* Non -epithelial
MLH1, MSH2, MSH6, PMS2
Lynch Syndrome
APC Familial Adenomatous
Polyposis (Gardner)
CDKN2A Melanoma-Astrocytoma or -
Pancreatic Syndrome
Summary of cancers associated with “newer” autosomal dominantly inherited cancer risk genes
Gene(s) Breast Ovarian Prostate Pancreatic Melanoma Colon Uterine Brain Kidney Stomach
ATM
BARD1
CHEK2
NBN
PALB2
BRIP1
RAD51C
RAD51D
Lynch:
Inherited (germline) mutations in a number of tumor suppressor genes may also lead to autosomal recessive inherited cancer susceptibility
Autosomal Recessive Cancer syndromes 101
Example of a typical Fanconi Anemia family
Autosomal recessive cancer syndromesGene(s) Syndrome Cancers
MUTYH MYH-associated polyposis Colorectal cancer
ATM* Ataxia telangiectasia Hematological malignancies
BLM Bloom Syndrome Hematological malignancies, gastric, colon, Skin SCCs
WAS Wiskott-Aldrich syndrome Hematological malignancies
NBN Nijmegen breakage syndrome Hematological malignancies,
medulloblastoma, glioma, rhabdomyosarcoma
FANCA, FANCB, FANCC*, BRCA2*, FANCD2, FANCE,
FANCF, XRCC9, FANCI, BRIP1*, FANCL, FANCM, PALB2*, RAD51C*, BRCA1*, REV7
Fanconi anemiaHematological malignancies,
SCCs (cervical, anal, HNSCCs, skin), medulloblastoma, Wilms tumor
TERT Dyskeratosis congenita Hematological malignancies, SCCs (cervical, anal, HNSCCs, skin)
SBDS Schwachman-Diamond syndrome Hematological malignancies,
MLH1*, MSH2*, MSH6*, PMS2*
Constitutional mismatch repair deficiency syndrome
Hematological malignancies, brain,embryonal tumors
DDB2, ERCC2, ERCC3, ERCC4, ERCC5 Xeroderma pigmentosum Skin SCCs, BCCs, and melanomas
WRN Werner syndrome Sarcoma, thyroid, melanoma
*Genes which also lead to increased cancer risk when monoallelic with autosomal dominant inheritance
Germline Cancer Genetics
Cancer risks
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
Cancer risks for BRCA1 and BRCA2 mutation carriers
http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA
Cancer risks for Lynch Syndrome (MLH1, MSH2, MSH6, PMS2)
Cancer risks for expanded list of breast and ovarian cancer genesBLACK: BREASTBLUE: OVARIAN
Green: RR 1Orange: 2-fold (moderate)Red: 4-fold (high)
Relative Risk BREAST OVARIAN
HIGH(>4-fold)
BRCA1BRCA2
CDKN2APTENPALB2TP53
BRCA1BRCA2BRIP1
RAD51CRAD51D
MSH2MSH6TP53
MODERATE(2-4 fold)
CDH1ATM
BARD1
ATMPALB2NBN
LOW(1-2 fold)
BRIP1CHEK2MSH2MSH6
NO ASSOC
APC, BLM, FANCM,FANCC, NBN, NF1,MLH1, MRE11A,PMS2, RAD50,
RAD51C, RAD51D,XRCC2
BARD1, CHEK2,FANCC, FANCM,MLH1, MRE11A,
PMS2, PTEN, RAD50
No DataAPC, BLM, CDKN2A,CDH1, FANCC, NF1,
XRCC2
Suszynska et al Gyn Onc 2019
Cancer risks for expanded list of colon cancer genes
Germline Cancer Genetics
Medical Management for carriers
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
Summary of medical management of cancer risk
Management of Cancer
Risk
Management of Cancer
Risk
ScreeningScreening
PreventionPrevention
Targeted TreatmentTargeted
Treatment
Family PlanningFamily
Planning
Summary of medical management for BRCA1/2 Carriers
Management of Cancer
Risk
Management of Cancer
Risk
ScreeningScreening
PreventionPrevention
Targeted TreatmentTargeted
Treatment
Family PlanningFamily
Planning
• Enhanced breast screening (MRI/mammo)• Ovarian cancer screening (TVUS/CA125)• Pancreatic cancer screening (EUS or MRCP)• Prostate cancer screening (PSA/DRE)
• Tamoxifen or raloxifene (breast)• Oral contraceptives (ovary)• Bilateral mastectomy• Salpingo-oophorectomy• Salpingectomy w/delayed oophorectomy
• Prenatal genetic diagnosis• Partner carrier screening (BRCA2)
• Platinum chemotherapy and/or PARP inhibitors
Summary of medical management in Lynch syndrome
Management of Cancer
Risk
Management of Cancer
Risk
ScreeningScreening
Preventive Surgery
Preventive Surgery
Targeted TreatmentTargeted
Treatment
Family PlanningFamily
Planning
• Enhanced colonoscopy screening• Ovarian cancer screening (TVUS/CA125)• Endometrial sampling• Urinalysis
• Aspirin (colon)• Oral contraceptives (ovarian)• Total abdominal hysterectomy• Salpingo-oophorectomy
• Prenatal genetic diagnosis• Partner carrier screening
• Immune checkpoint blockade
Germline Cancer Genetics
Cancer genetic testing 2020
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
Adult cancer risk evaluation -2020
Many more genes with more options for ordering, including custom panel orders
Until 2013…
-> Take home: you cannot assume what genes have been evaluated unless you see the report
How your patient may find out they have a mutation Traditional Genetic Testing
• Meet with a cancer genetic counselor (GC) for pre-test counselling -> GC orders genetic testing -> meet with GC for post-test counselling -> meet with MD to come up with medical management plan
• May incorporate web-based or telegenetics
Point of Care testing• For cancer patients: Provider (ie oncologist) discusses genetic testing briefly (video, pamphlet) -> Provider
orders genetic testing -> meet with GC and Genetics MD only if positive result, VUS, confusing results, patient request
• Proposed for Ashkenazi Jewish individuals: population based screening, for example with gynecologist
Somatic testing -> germline testing• Mutation in a cancer risk gene found on tumor testing -> recommended followup
Research study enrollment (ie Geisinger biobank) -> incidental findings
Direct to consumer testing
Direct to Consumer Genetic Testing
Somatic Cancer Genetics
Treatment Implications
“Somatic” or “driver” changes that lead to cancer progression
Types of somatic alterations
Biological Function:“Phenotype”
Single mutation testingSingle gene testingMulti-gene testing (NGS)DNA :“Genotype”
RNA:“Gene Expression”
Protein: “Protein Expression”
SNP arraysCytogeneticsFISH
RT-PCRMicroarray
ImmunohistochemistryImmunofluorescenceWestern blotELISA
Signature-type assay
Some examples of FDA approved targeted therapies based on somatic genetic testing in solid tumors – by alteration
Genetic alteration Cancer FDA Approved Targeted therapiesEGFR exon19 and exon 21 mutations
Lung afatinib (Gilotrif), gefitinib (Iressa), osimertinib (Tagrisso), erlotinib (Tarceva)
BRAF V600E, V600K mutations Melanoma Lung
V600E only - vemurafenib (Zelboraf)dabrafenib (Tafinlar), trametinib (Mekinist)
MET exon 14 skipping Lung capmatinib (Tabrecta)ALK rearrangements Lung crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa)
ERBB2 amplification Breast trastuzumab (Herceptin), ado-trastuzumab-emtansine(Kadcyla), pertuzumab (Perjeta)
PIK3CA mutations Breast alpelisib (Piqray)KRAS and NRAS wildtype (no mutations
Colorectal KRAS only - cetuximab (Erbitux)KRAS and NRAS – panitumumab (Vectibix)
FGFR2 rearrangementsFGFR2/FGFR3 mutations
CholangiocarcionomaBladder
pemigatinb (Pemazyre)erdafitinib (Balversa)
BRCA1/BRCA2, other DNA repair mutations
Ovarian, Prostate, Breast olaparib (Lynparza), rucaparib (Rubraca), veliparib (no brand), talozaparib (Talzenna)
Tumor agnostic approvals – a new territory for the FDA
Genetic alteration FDA Approved Targeted therapies
Tumor mutational burden highMicrosatellite instability highMismatch repair deficient
pembrolizumab (Keytruda)
NTRK gene fusion larotrectinib (Vitrakvi)entrectinib (Rozlytrek)
Somatic Cancer Genetics
Somatic Genetic Testing in 2020
“Somatic” or “driver” changes that lead to cancer progression
Major Tumor Genetic testing platforms
Academic Platforms• Some Northeast examples:
– Memorial Sloan Kettering’s “IMPACT”– Penn Medicine “CPD”
Company Platforms• Foundation Medicine• Caris Life Sciences
Just to make it more confusing… enter Liquid Biopsy
“Germline” or “constitutional”
genetic changes that lead to cancer predisposition
“Somatic” or “driver” changes that lead to cancer progression
Cell-free (cfDNA) is derived from:- Lymphocytes- Many disease states (ESRD, CVA, MI, surgery, trauma)- Fetal-derived- Non-human sources- Tumor-derived (ctDNA)
Proportion of ctDNA in cfDNA?- Huge range- Can be none or <1%- Maybe as high as 90%
Blood -> LymphocytesTumor
Both germline and liquid biopsy based testing can be confounded by CHIPCHIP (Clonal hematopoiesis of indeterminate potential)- acquired somatic mutations in
lymphocytes
- Frequency increases with age (~15% of >80yo)
- Leads to mutations in blood-based testing may be due to CHIP and not be inherited
- Associated with increased risk of cardiovascular disease and hematological malignancies
Germline variants (GV)Inherited from parents, found in egg and sperm
De novo Variants (DNV)Arise in the embryo OR de novo in the parents’ egg or sperm
Post-zygotic Variants (PZV)Arise during embryo development
CHIP Variants (CHIPV)Arise just in lymphocytes mostly during aging
Genetic Testing Results = GV + DNV + PZV + CHIPV
Summary of Cancer Genetic Testing - 2020
Germline Testing Tumor Testing Liquid Biopsy
Companies (examples)
Ambry, GeneDx, Invitae, Myriad Caris, Foundation Foundation
What is sequenced?
Blood lymphocytes (from whole blood or saliva)
Tumor (and sometimes matched blood)
Blood plasma (from whole blood)
What mutations can you get?
Germline (inherited)De novoPost-zygoticAcquired lymphocyte (CHIP)
All on germline testingPLUSTumor mutations(lab may subtract germline mutations)
All on germline testingPLUSTumor mutations IF the circulating tumor fraction is high enough
Online Resources
ASCO Meeting Library• https://meetinglibrary.asco.org/
ACMG Guidelines• Cancer Risk Referral guidelines:
https://www.acmg.net/docs/ACMG_Practice_Guideline_Referral_Indications_for_cancer_predisposition.pdf
NCCN guidelines • https://www.nccn.org/ - (Need free login) - Genetic/Familial High-Risk Assessment: Breast and
Ovarian , Genetic/Familial High-Risk Assessment: Colorectal , Prostate Cancer Early Detection
NCI (Cancer.gov)• https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-
sheet